Project Summary/Abstract Mitragyna speciosa (kratom) is a plant indigenous to Southeast Asia with over 40 bioactive alkaloids, two of which, mitragynine (MG) and 7-hydroxymitragynine (HMG), act at mu opioid receptors (MORs). Use of kratom and kratom products increased in the US contemporaneous a critical change-point in the opioid crisis (when painkiller prescribing became more conservative), with many US adults initiating kratom use for putatively therapeutic indications, such as mitigation of withdrawal from prescribed or nonprescribed opioids, and as a self-treatment for symptoms of pain, fatigue, or psychiatric or substance use disorders (SUDs). The number of US users in the past few years is likely >10 million—and increasing. Yet we have little understanding of the balance of, or determinants of, beneficial or adverse effects of kratom either proximal to use (e.g., sedation, nausea, analgesia) or over time (e.g., symptoms of SUD). Preclinical work shows that MG and HMG act as partial biased at MORs but also have non-opioid mechanisms of action and that these and other alkaloids may have therapeutic potential for the treatment of pain and SUDs with less risk than traditional opioids. This converges with self-report data, where there is remarkably consistent therapeutic benefit attributed to kratom with minor-moderate side effects and fewer indicators of abuse potential than might be expected from a substance that, for some, reportedly substitutes for opioids. Yet this work is limited to cross-sectional surveys, case reports, and social-media analyses, which may suffer from self-selection and recall bias and sheer lack of information. Many large surveys of regular users are outdated, given rapid expansion of kratom products, and diverge from findings in smaller samples, particularly with respect to prevalence of kratom addiction and withdrawal. Given kratom’s complex pharmacology and novelty (in the US), and the accompanying near- vacuum in policy and in clinical recommendations, more work is needed to understand its risks and potential benefits. So, too, is scientific consilience in developing a systematic line of kratom research. The aims of this K99/R00 work towards both. For the K99, we aim to, using a sample of kratom-using US adults: (1) conduct momentary assessment of individual instances of kratom product use in daily life; (2) determine associations of momentary responses with directly assayed content of samples of participants’ kratom products; (3) evaluate relationships among kratom effects (including withdrawal-like effects), the kratom products used, and alkaloid concentrations in biospecimens; (4) explore narrative accounts of kratom use. For the R00, I will (5) systematically evaluate effects of kratom discontinuation. Collectively, these studies will be a bridge to randomized interventional studies to be proposed in an R01. These studies also begin the interdisciplinary and interinstitutional collaboration I believe is needed i...